Article

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Department of Laboratory Medicine and Pathobiology, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2011; 121(5):1917-29. DOI: 10.1172/JCI43615
Source: PubMed

ABSTRACT

Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr-/- mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr-/- mice by generating Gcgr-/-Glp1r-/- mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr-/-Glp1r-/- mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr-/- mice. Unexpectedly, deletion of Glp1r in Gcgr-/- mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr-/-Glp1r-/- islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr-/-Glp1r-/- islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr-/-Glp1r-/- mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.

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    • "AR231453, an orally active agonist at GPR119 receptors potentiates glucose-induced insulin secretion from mouse islets, and this stimulatory effect is lost following GPR119 deletion (Chu et al., 2007). GPR119 is up-regulated in islets from mice with global deletion of glucagon receptors and GLP-1 receptors, and these mice show increased sensitivity to AR231453 (Ali et al., 2011), suggesting that β-cells can compensate for disruption in signalling through the glucagon and GLP-1 insulinotropic receptors by increasing the expression of GPR119, another receptor coupled to Gs-induced cAMP elevation. There is no information on whether GPR119 regulates glucagon or somatostatin secretion. "
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